KATP opener-induced delayed cardioprotection: involvement of sarcolemmal and mitochondrial KATP channels, free radicals and MEK1/2

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Title KATP opener-induced delayed cardioprotection: involvement of sarcolemmal and mitochondrial KATP channels, free radicals and MEK1/2
Author Gross, Eric R.; Peart, Jason Nigel John; Hsu, Anna K.; Grover, Gary J.; Gross, Garrett J.
Journal Name Journal of Molecular and Cellular Cardiology
Year Published 2003
Place of publication United States
Publisher Academic Press
Abstract Previous studies have demonstrated the importance of the sarcolemmal and/or the mitochondrial KATP channel (sKATP and mKATP, respectively) in mediating delayed cardioprotection induced by opioids, bradykinin, adenosine or the KATP-channel opener (KCO), diazoxide. However, the ability of other KCOs, such as the putative sKCO P-1075 or the putative mKCO BMS-191095, to induce delayed cardioprotection has not been tested. In this study, rats were randomly divided and treated with P-1075 (1 μg/kg), BMS-191095 (BMS, 1 mg/kg), diazoxide (3.5 mg/kg) or vehicle. Selective blockers were also administered 5 min prior to KCO or vehicle. These included the sKATP antagonist (HMR-1098 (HMR, 6 mg/kg)), the mKATP antagonist (5-hydroxydecanoic acid (5-HD, 10 mg/kg)), the oxygen radical scavenger (N-2-mecaptopropionyl-glycine (2-MPG, 20 mg/kg)) or the MEK1/2 inhibitor (PD-98059 (PD, 1 mg/kg)). Twenty-four hours later, rats were subjected to 30-min ischemia and 2-h reperfusion, followed by infarct size assessment. P-1075, BMS or diazoxide treatment produced similar reductions in infarct size as compared to vehicle (37.2 ± 2.3%*, 40.7 ± 1.5%*, 35.6 ± 3.6%* vs. 59.8 ± 1.8%, P < 0.05, respectively). HMR administration before P-1075 and diazoxide abolished delayed cardioprotection, but not BMS-induced infarct size reduction (56.1 ± 1.1%, 54.9 ± 3.3%, 41.0 ± 1.7%*, respectively). Administration of 5-HD, 2-MPG or PD prior to the three KATP openers abolished delayed cardioprotection. These data imply BMS-191095 has a selective mitochondrial site of action, perhaps the mKATP channel, whereas diazoxide and P-1075 affect both the sKATP and mKATP channels. All three KCO also require an initial oxygen-derived free radical (OFR) burst and MEK1/2 activation to trigger delayed cardioprotection.
Peer Reviewed Yes
Published Yes
Publisher URI http://www.elsevier.com/wps/find/journaldescription.cws_home/622889/authorinstructions
Alternative URI http://dx.doi.org/10.1016/S0022-2828(03)00183-4
Volume 35
Issue Number 8
Page from 985
Page to 992
ISSN 0022-2828
Date Accessioned 2006-07-26
Date Available 2009-12-21T06:46:45Z
Language en_AU
Research Centre Griffith Health Institute; Heart Foundation Research Centre
Faculty Griffith Health Faculty
Subject PRE2009-Clinical Pharmacology and Therapeutics
URI http://hdl.handle.net/10072/27879
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1x

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